This invention relates to copolymers of aromatic anhydrides and aliphatic esters. More specifically, it relates to copolymers of aromatic anhydrides and aliphatic esters particularly well suited for melt processing to prepare biomedical devices, especially wound closure devices.
Polymers of aliphatic and aromatic anhydrides have been extensively studied for many years. As long ago as the 1930's, Carothers had prepared a series of aliphatic polyanhydrides for use as fibers in the textile industry (see J. Am. Chem. Soc., 54, 1569 (1932)). Later, in the mid 1950's, Conix was able to synthesize aromatic polyanhydrides with improved film and fiber forming properties (see J. Polym. Sci., 29 343 (1958)). However, these early attempts to make polyanhydrides with outstanding properties were unsuccessful because these polyanhydrides exhibited poor thermal and hydrolytic stability. Therefore, during this time, no commercial applications of polyanhydrides were found.
More recently polyanhydrides with sustained drug release properties have been made. U.S. Pat. No. 4,757,128, and Domb et al., J. of Polymer Sci., 25, 3373 (1987), disclose the preparation of polyanhydrides from pure, isolated prepolymers of diacids and acetic acid under well defined polymerization reaction conditions of temperature and time, optionally in the presence of a coordination catalyst. The molecular weight of the polyanhydrides prepared from the isolated prepolymers is reported to be higher than that achieved when an unisolated prepolymer mixture is used. However, as stated by Domb et al., the polyanhydrides depolymerize to form a rubbery gel if the polymerization temperature is maintained at elevated temperatures for an extended period of time.
The synthesis techniques described by Domb have lead to the use of polyanhydrides as biodegradable matrices for the controlled release of biologically active substances. See, for example, U.S. Pat. No. 4,857,311, and U.S. Pat. No. 4,888,176. One of the factors which make a polyanhydride particularly well suited as a biodegradable matrix is that it breaks down into biocompatible degradation products based on the monomeric diacids when exposed to moist bodily tissue for extended periods of time. These biocompatible degradation products can be readily passed through the tissue without any significant tissue response or harm to the digestive or vascular systems.
Recent attempts have been made to optimize the synthesis of anhydride copolymers. Specifically, anhydride copolymers which will exhibit longer release and degradation times when used as a matrix for drug release have been studied. U.S. Pat. No. 4,789,724 describes preparing copolymers from individually prepared, isolated prepolymers. Domb, Macromolecules, 25, 12 (1992), describes preparing relatively low molecular weight (I.V.&lt;0.45 dl/g) aromatic copolymers of anhydrides which are highly soluble in conventional solvents, and therefore suitable for the preparation of solvent cast drug release devices.
Although the extensive studies performed by Domb and his colleagues, as described above, have shown the feasibility of preparing cert in polyanhydrides which are suitable as matrices for drug release, this significant class of polyanhydrides are unsuitable for numerous biomedical applications, especially for the preparation of implantable devices for wound closure. Upon a careful review of Domb's work, it becomes apparent that Domb was able to prepare aliphatic polyanhydrides of high molecular weight, but the reported values for the molecular weight of polyanhydrides which are predominately aromatic are too low for conventional melt processing techniques required to make biomedical devices. Although it is possible to prepare drug delivery devices from aliphatic polyanhydrides, it is most likely that it would not be possible to make biomedical devices from the aliphatic polyanhydrides described in Domb due to their poor thermal stability. However, it would be highly desirable to fabricate devices from polymers which can withstand the effects of melt processing and sterilization using conventional melt processing and irradiation techniques. In this regard, the incorporation of aromatic functionality in the polymer chains of the polyanhydride is critical for the application of melt processing to fabricate biomedical devices or the application of irradiation to achieve sterilization. See, for example, U.S. Pat. Nos. 4,435,590, 4,510,295, and 4,546,152, which describe the preparation of polymers for biomedical applications with a high degree of aromatic functionality capable of withstanding the effects of irradiation for sterilization.
Other polymer compositions containing anhydride functionality have been described in the literature. For example, U.S. Pat. No. 4,414,381 describes the preparation of aromatic poly(ester-anhydride) copolymers. These copolymers are described as being melt processable, and useful for preparing fibers, films and molding powders. Unfortunately, these copolymers are not bioabsorbable, and therefore are unsuitable for numerous implantable, medical device applications.
The failure of Domb and others to synthesize bioabsorbable, aromatic polyanhydride polymers with high molecular weights limits the suitability of such polyanhydrides to their use as biomedical devices. Additionally, it would be highly desirable to develop aromatic polyanhydride containing polymers, such as aliphatic polyesters, which were quickly absorbable in vivo. In view of these deficiencies, it would be most desirable if an aromatic polyanhydride copolymer could be developed which was bioabsorbable. Accordingly, it would be desirable to prepare copolymers that contain an aromatic polyanhydride which exhibits the requisite bioabsorbability for the preparation of biomedical devices, especially using melt processing techniques such as injection or extrusion molding. Likewise, it would be desirable to prepare copolymers that contain aromatic polyanhydrides which have outstanding thermal and dimensional stability at elevated temperatures for prolonged periods, and the ability to maintain physical and biological properties upon sterilization using conventional irradiation techniques. All of these properties would be most beneficial in a bioabsorbable polymer which contains an aromatic polyanhydride for the preparation of biomedical devices, especially implantable wound closure devices and adhesion prevention barriers which are absorbable in bodily tissue without causing adverse tissue response or other adverse reactions.